We report a case of recurrence of herpes simplex virus (HSV) keratouveitis following the intravitreal injection of bevacizumab for macular edema secondary to central retinal vein occlusion (CRVO) in a previously adequately treated patient of herpetic keratouveitis. A 47-year-old man with the previous history of HSV keratouveitis was administered 2 doses of intravitreal bevacizumab in the right eye for CRVO, at an interval of 4 weeks. Following the second dose, the patient developed decreased vision, corneal edema, and anterior segment inflammation. Since he was a previously known case of HSV keratouveitis with a positive polymerase chain reaction for HSV from the aqueous, oral valacyclovir was started along with topical steroids and cycloplegics. He showed a good response to treatment with resolution of keratouveitis. This case demonstrates that the recurrence of herpetic keratouveitis can be a possible complication of intravitreal bevacizumab, which may occur even after prior uneventful injections.

The indications for the use of intravitreal antivascular endothelial growth factor (anti-VEGF) agents are growing by the day and with increased usage come the risk of increased complications and side effects. We report a case of recurrence of herpes simplex virus (HSV) keratouveitis following intravitreal injection of bevacizumab in a previously treated patient of HSV keratouveitis. To the best of our knowledge, there is no existing report in the literature of recurrence of HSV keratouveitis following intravitreal anti-VEGF.

Case Report

A hypertensive man in his mid-40s, presented with blurring of vision in his right eye for 2 days. Pupillary reactions were normal. His best-corrected visual acuity (BCVA) was 20/40 in the right eye and 20/20 in the left eye with intraocular pressures of 14 and 10 mmHg, respectively. Anterior segment examination was unremarkable except, for the presence of a few old pigmented keratic precipitates (KPs) in the right eye with no flare or cellular reaction. Indirect ophthalmoscopy of the right eye revealed dilatation and tortuosity of retinal veins with hemorrhages in all quadrants consistent with the diagnosis of Central CRVO. Optical coherence tomography showed an increase in central macular thickness with cystoid macular edema. History revealed an episode of adequately treated HSV keratouveitis (polymerase chain reaction positive for HSV Type 1 from the aqueous), 1 year before the present symptoms. He was counseled for the need of anti-VEGF injections and was given the first dose of intravitreal bevacizumab (Avastin, Genentech, Inc., USA) (1.25 mg/0.05 ml). Due to persistence of macular edema, the second intravitreal injection was administered after 1 month.

After the second dose, the patient reported back the next day with complaints of pain and decreased vision in his right eye. His vision had dropped to 20/100, and anterior segment examination revealed stromal edema, multiple KP's, and 2+ cellular reaction [Figure 1]. Based on the characteristic anterior segment findings and previous clinical history, a diagnosis of recurrence of HSV keratouveitis was made. Oral valcyclovir (1 g three times a day) was restarted along with topical corticosteroids and cycloplegics. The patient responded well to treatment with the resolution of stromal and anterior segment inflammation. At the last follow-up, 3 months later, his BCVA was 20/40 with minimal cellular reaction in the anterior segment. Posterior segment showed straightening of the vascular arcades with decrease in retinal hemorrhages and macular edema.

Figure 1: Anterior segment photograph of the right eye after 2nd dose of bevacizumab, revealing stromal haze with keratic precipitates

Herpetic corneal disease remains an enigma till date. Following primary infection, HSV can maintain latency in the trigeminal ganglion and cornea.[1] Stress, trauma, surgery and immunocompromised states potentially predispose to the recurrence of ocular HSV disease. VEGF production has been demonstrated from corneal epithelial cells[2] and an increase in production occurs following HSV infection.[3] Based on these findings, it was postulated by Khalili et al.[4] that blocking VEGF with anti-VEGF agents may lead to reactivation of the virus in eyes previously exposed to HSV. They also reported a case of HSV epithelial keratitis developing de novo after intravitreal bevacizumab given for proliferative diabetic retinopathy.

The present case was associated with the recurrence of HSV keratouveitis within 24 h of the second dose of intravitreal bevacizumab. The exact cause of the recurrence, whether attributable to the stress of surgical procedure or to anti-VEGF agent itself may be difficult to determine with certainty as HSV keratitis has also been reported to occur after intravitreal triamcinolone.[5],[6]

This case highlights the importance of counseling patients with prior HSV infection, regarding the risk of reactivation following anti-VEGF. With the increasing use of anti-VEGF agents, the role of VEGF in corneal inflammation and healing also requires further attention.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.